Background: Congenital portosystemic shunt (cPSS) is one of the most common congenital disorders diagnosed in dogs. Hepatic encephalopathy (HE) is a frequent complication in dogs with a cPSS and is a major cause of morbidity and mortality. Despite HE been a major cause of morbidity in dogs with a cPSS, little is known about the cellular changes that occur in the central nervous system of dogs with a cPSS. Objectives: The objective of this study was to characterise the histological changes in the cerebral cortex and cerebellum of dogs with cPSS with particular emphasis on astrocyte morphology. Methods: Eight dogs with a confirmed cPSS were included in the study. Results: Six dogs had substantial numbers of Alzheimer type II astrocytes and all cases had increased immunoreactivity for glial fibrillary acidic protein in the cerebral cortex, even if there were minimal other morphological changes. Conclusions This study demonstrates that dogs with a cPSS have marked cellular changes in the cerebral cortex and cerebellum. The cellular changes that occur in the cerebral cortex and cerebellum of dogs with spontaneously arising HE are similar to changes which occur in humans with HE, further validating dogs with a cPSS as a good model for human HE.

PURPOSE: Alcohol has been associated with 10%-35% trauma admissions and 40% trauma-related deaths globally. In response to the COVID-19 pandemic, the United Kingdom entered a state of "lockdown" on March 23, 2020. Restrictions were most significantly eased on June 1, 2020, when shops and schools re-opened. The purpose of this study was to quantify the effect of lockdown on alcohol-related trauma admissions. METHODS: All adult patients admitted as "trauma calls" to a London major trauma centre during April 2018 and April 2019 (pre-lockdown, n = 316), and 1st April-31st May 2020 (lockdown, n = 191) had electronic patient records analysed retrospectively. Patients' blood alcohol level and records of intoxication were used to identify alcohol-related trauma. Trauma admissions from pre-lockdown and lockdown cohorts were compared using multiple regression analyses. RESULTS: Alcohol-related trauma was present in a significantly higher proportion of adult trauma calls during lockdown (lockdown 60/191 (31.4%), vs. pre-lockdown 62/316 (19.6%); (odds ratio (OR): 0.83, 95% CI: 0.38-1.28, p < 0.001). Lockdown was also associated with increased weekend admissions of trauma (lockdown 125/191 weekend (65.5%) vs. pre-lockdown 179/316 (56.7%); OR: 0.40, 95% CI: 0.79 to -0.02, p = 0.041). No significant difference existed in the age, gender, or mechanism between pre-lockdown and lockdown cohorts (p > 0.05). CONCLUSIONS The United Kingdom lockdown was independently associated with an increased proportion of alcohol-related trauma. Trauma admissions were increased during the weekend when staffing levels are reduced. With the possibility of further global "waves" of COVID-19, the long-term repercussions of dangerous alcohol-related behaviour to public health must be addressed.
Adult ; COVID-19/epidemiology* ; Cohort Studies ; Communicable Disease Control ; Humans ; London/epidemiology* ; Pandemics ; Retrospective Studies ; Trauma Centers

The cofactor nicotinamide adenine dinucleotide (NAD⁺) plays a key role in a wide range of physiological processes and maintaining or enhancing NAD⁺ levels is an established approach to enhancing healthy aging. Recently, several classes of nicotinamide phosphoribosyl transferase (NAMPT) activators have been shown to increase NAD⁺ levels in vitro and in vivo and to demonstrate beneficial effects in animal models. The best validated of these compounds are structurally related to known urea-type NAMPT inhibitors, however the basis for the switch from inhibitory activity to activation is not well understood. Here we report an evaluation of the structure activity relationships of NAMPT activators by designing, synthesising and testing compounds from other NAMPT ligand chemotypes and mimetics of putative phosphoribosylated adducts of known activators. The results of these studies led us to hypothesise that these activators act via a through-water interaction in the NAMPT active site, resulting in the design of the first known urea-class NAMPT activator that does not utilise a pyridine-like warhead, which shows similar or greater activity as a NAMPT activator in biochemical and cellular assays relative to known analogues.